Pharmaceutical composition for prevention and treatment of mental disease with enhanced nmdar function

ABSTRACT

The present invention relates to a pharmaceutical composition for improving a sociability behavior in a patient having a mental disease with an enhanced NMDAR function.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.14/966,706, filed on Dec. 11, 2015, which claims the benefit of KoreanPatent Application No. 10-2015-0091560, filed on Jun. 26, 2015 in theKorean Intellectual Property Office, the entirety of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a pharmaceutical composition forprevention and treatment of a mental disease with an enhanced N-methylD-aspartate (NMDA) receptor (“NMDAR”) function.

2. Description of the Related Art

One of the most characteristic symptoms shown by patients having mentaldiseases such as Autism spectrum disorder, Schizophrenia and attentiondeficit/hyperactivity disorder (ADHD) is a significantly deficientsociability behavior, in which a person takes interest in anotherperson, makes conversations and interacts. Therefore, drugs forimproving the sociability behaviors of the patients having mentaldiseases have been researched (Korean Unexamined Patent 10-2014-0132493(Nov. 18, 2014)).

However, the causes of Autism spectrum disorder, Schizophrenia,attention deficit/hyperactivity disorder (ADHD), etc. are not completelyidentified, and the symptoms and conditions of patients vary, so evendrugs that improve sociability behavior deficiency of specific patientsdoes not have effects on other patients.

Accordingly, the applicants of the present invention have identified,while researching sociability behavior deficiencies, that sociality canbe improved by administrating NMDAR inhibitors in the case of mentaldiseases with an enhanced NMDAR function.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a pharmaceuticalcomposition for improving sociability behaviors in a patient having amental disease with an enhanced NMDAR function.

To achieve the object, the present invention provides a pharmaceuticalcomposition for prevention and treatment of a mental disease with anenhanced NMDAR function, the pharmaceutical composition including anNMDAR inhibitor.

The present invention improves the sociability behavior of a patienthaving a mental disease with an enhanced NMDAR function.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a behavior experiment box used for a 3-chamber sociabilitytest.

FIG. 2 shows an experimental result of wild-type mice and brain-specificangiogenesis inhibitor 1-associated protein 2 (“IRSp53”) deficient mice.

FIGS. 3 and 4 show sociability behavioral changes of mice when memantineand 2-Methyl-6-(phenylethynyl)pyridine (“MPEP”) are administered to theIRSp53 deficient mice, respectively.

FIG. 5 shows the change in NMDAR activation when the memantine and theMPEP are administered to the IRSp53 deficient mice.

FIG. 6 shows the result of synaptic structural and functional analysisof an inner prefrontal cortex of the IRSp53 deficient mice.

FIG. 7 shows the change in nerve cell firing of the inner prefrontalcortex when the memantine is administered to the IRSp53 deficient mice.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition forprevention and treatment of a mental disease with an enhanced an NMDARfunction, the pharmaceutical composition including an NMDAR inhibitor.

In addition, the present invention relates to a pharmaceuticalcomposition for improving sociability behaviors in a patient having amental disease with an enhanced NMDAR function, the pharmaceuticalcomposition including an NMDAR inhibitor.

Hereinafter, the present invention is described in detail.

NMDAR

N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a specific receptor of aglutamate which is one of main neurotransmitters of an excitatorysynapse.

NMDAR Inhibitor

The NMDAR inhibitor signifies medicine suppressing an NMDAR function.The NMDAR inhibitor may be memantine, MPEP, MK-801 (Dizocilpine) or2-amino-5-phosphonopentanoic acid (“AP5”). The MK-801 is anoncompetitive inhibitor of the NMDAR and binds to an ion binding siteto inhibit a receptor function, and AP5 is a selective inhibitor of theNMDAR and binds to a glutamate binding site.

Mental Disease with an Enhanced NMDAR Function

In the present invention, “enhanced NMDAR” signifies that the NMDARfunction is more enhanced than a normal person. This may be due toover-expression, enhanced protein functions, etc. The mental diseasewith the enhanced NMDAR function involves IRSp53 gene damage. In thiscase, the IRSp53 gene damage signifies that, due to expressionsuppression, expression disable, mutant, etc. of the IRSp53 gene, anormal level gene expression is difficult.

The mental disease with the enhanced NMDAR function of the presentinvention has a sociability behavior deficient symptom. The sociabilitybehavior deficiency signifies the generally used sociability behaviordeficiency in metal diseases such as autism. In other words, thesociability behavior deficiency includes deficiency of socialinteractions and social communications, thus indicates difficulty ofsocial interpersonal relations. In addition, the mental disease with theenhanced NMDAR function is any one disease selected from the groupconsisting of autism, schizophrenia and ADHD.

Patient Having the Mental Disease with the Enhanced NMDAR Function

The patient having the mental disease with the enhanced NMDAR functionof the present invention indicates a patient diagnosed with the mentaldisease with the enhanced NMDAR function. In other words, they arepatients having the enhanced NMDAR function among patients having mentaldiseases of autism, schizophrenia, ADHD, etc.

Pharmaceutical Composition

The pharmaceutical composition of the present invention includes theNMDAR inhibitor. The pharmaceutical composition is for the preventionand treatment of the mental disease with the enhanced NMDAR function orfor the improvement of sociability behavior of patients having themental disease with the enhanced NMDAR function.

The pharmaceutical composition of the present invention targets patientshaving the enhanced NMDAR function among patients having autism,schizophrenia, attention deficit/hyperactivity disorder, etc. exhibitingsociability behavior deficiency symptoms. In addition, the compositionof the present invention targets diseases involving the enhanced NMDARfunction among diseases of autism, schizophrenia, attentiondeficit/hyperactivity disorder, etc. having sociability behaviordeficiency symptoms.

The pharmaceutical composition of the present invention may include 0.01to 99.99 parts by weight of the NMDAR inhibitor based on 100 parts byweight of the composition, and may preferably include 60 to 98 parts byweight. More preferably, the pharmaceutical composition of the presentinvention may include 90 to 95 parts by weight of the NMDAR inhibitorbased on 100 parts by weight of the composition. However, this may beincreased or decreased according to the needs of the person to beadministrated, and may be adequately increased or decreased according toconditions of dietary life, nutrition state, progression of the disease,amount of sociability behavior deficiency, etc. In addition, thepharmaceutical composition of the present invention may form the NMDARinhibitor into an appropriate form along with a pharmaceuticallyallowable carrier. ‘Pharmaceutically allowable’ signifies a compositionwhich does not generally cause allergic reactions such asgastrointestinal disorders, dizziness, etc. or similar reactions whenthe composition is physiologically allowed and administered to a person.

The pharmaceutical composition of the present invention may beadministered orally or parenterally, and may be generally used in a formof a pharmaceutical medicine. A pharmaceutical preparation preferablyincludes an oral administration preparation such as a tablet, a soft orhard capsule, liquid, a suspension, etc. and the pharmaceuticalpreparation may be prepared by using the pharmaceutically allowablecarrier, for example, in the case of the oral administrationpreparation, excipients, binders, disintegrants, glydents, solubilizers,suspending agent, preserved agents, extenders, etc.

The administration amount of the pharmaceutical composition of thepresent invention may be determined by an expert according to variousfactors such as the state, age, sex, complications, etc. of the patient,and generally, 0.1 mg to 10 g per 1 kg, and more preferably 5 g per 10mg may be administered for an adult. In addition, 1 day amount or ½, ⅓or ¼ amount of the 1 day amount of the pharmaceutical composition may beincluded in a dosage unit, and the pharmaceutical composition may beadministered 1 to 6 times a day. However, in the case of a long-termintake for the purpose of health and hygiene or the purpose of adjustinghealth, the administration amount may be lower than the described range,because the active component is safe, the administration amount may begreater than the described range.

Advantages and features of the present invention, and method forachieving thereof will be apparent with reference to the examples thatfollow. But, it should be understood that the present invention is notlimited to the following embodiments and may be embodied in differentways, and that the embodiments are given to provide complete disclosureof the invention and to provide thorough understanding of the inventionto those skilled in the art, and the scope of the invention is limitedonly by the accompanying claims and equivalents thereof.

<Material and Method>

For the experiment animals of the present invention, wild-type micebackcrossed into a C57BL/6J background and IRSp53 deficient mice wereused. The mice were at 2-4 months of age. In addition, in the presentinvention, all of the experiments were conducted by maintaining atemperature of 20-22° C. and a humidity of 30-40% while the lights areturned on during 7:00 am to 7:00 pm.

The IRSp53 deficient mice were used in the experiment by making the micefrom the method disclosed in Kim, M. H. et al. (Enhanced NMDAReceptor-Mediated Synaptic Transmission, Enhanced Long-TermPotentiation, and Impaired Learning and Memory in Mice Lacking IRSp53. JNeurosci 29, 1586-1595, doi:Doi 10.1523/Jneurosci.4306-08.2009). Inother words, a particular gene trap cassette was inserted between Exon 3and Exon 4, which encode the gene sequence expressing the actual proteinamong the IRSp53 gene (NCBI number: NM_001037755), such that anarbitrarily different sequence is inserted into the original sequence tochange the entire sequence, so the gene is not expressed normally, andas a result, the IRSp53 gene expression is suppressed.

As the memantine, which is an NMDAR inhibitor and the MGluR inhibitor,the MPEP indirectly inhibiting the NMDAR is dissolved in physiologicalsaline and used. The memantine is used in a concentration of 10 mg (10mg/kg) per unit weight, and the MPEP is used in a concentration of 30 mg(30 mg/kg) per unit weight, and the drug was administered to theexperiment mice by intraperitoneal injection before 30 minutes of everyexperiment.

Experimental Example 1

NMDAR was tested with respect to the sociability behavior ofhyperactivated mice. The 3-chamber sociability test and the directinteraction test, which are the most widely used among the behavioralexperiments for identifying sociability behavior of mice. The 3-chambersociability test was conducted by using a behavior experiment boxseparated into 3 sections. FIG. 1 shows a drawing of an experiment boxused for the 3-chamber sociability test. A, B, and C of FIG. 1 show themeasurement based on the box bottom, the horizontal side surface and thevertical side surface, respectively, and the experiment box wasmanufactured exposing that the top so the experiment may be photographedby a camera (FIG. 1). In the basic 3-chamber sociability test, a mouse(stranger) was placed in one side and an object (small toy block)without scent was placed in the other side, and the normal mouse (WT)and the deficient mouse were placed in the middle chamber to observe howmuch attention was given to the other mouse and explored and time wasspent.

The detailed experiment method of the present invention is describedbelow. First, the wild-type mouse and the IRSp53 deficient mouse wereprepared. In addition, before 10 minutes of the experiment, the mouse tobe experimented was put into a soundproof booth in which the experimentwas to be conducted. 10 minutes later, the holes in the inner wall wereblocked and the mouse was put into the middle area. Another 10 minuteslater, the holes were opened, and the mouse was allowed to move freelyaround the 3 chambers. Then, another mouse (Stranger 1) was put into acylindrical plastic cup, through which a hole was punctured at a sidesurface, and the cup was placed upside-down at a corner of one side ofthe two areas. In the opposite area, a plastic cup, in which objectssuch as a triangular cone and the like was placed, was placedupside-down. Then, the mice, which are the target of the experiment,were allowed to move around freely for 10 minutes.

Lastly, the object in the cup, in which the object was placed, wasremoved, and a new mouse (Stranger 2) was put into the cup, and themouse, which is the target of the experiment, was allowed to move freelyfor 10 minutes.

In this case, by using the strangers 1 and 2, which are wild-type micecapable of conducting normal growth and sociability behavior, theexperiment was designed and conducted such that only the sociabilitybehaviors of the wild-type mice and the IRSp53 gene deficient mice,which are the targets of the experiment, were compared.

The analysis method to obtain the experiment result will be describedbelow.

During 10 minutes of experiment where the Stranger 1 and the object wereplaced, the time of the mouse staying at the two areas were measured. Inaddition, to measure the time of the actual mice exploring the stranger1 or the object, the time when the nose of the mouse crosses over avirtual line 2 cm away from the plastic cup was measured. Based on thisnumber, a preference index showing the sociability behavior was derived.The calculation equation of the preference index is as <Equation 1> to<Equation 3>.

In addition, the same analysis was also conducted for 10 minuteexperiment performed with the Stranger 1 and Stranger 2.

Preference index (%)={(Time staying in Stranger 1 area−Time staying inthe object area)/(Time staying in Stranger 1 area+Time staying in theobject area)}×100  <Equation 1>

Preference index (%)={Time of the nose crossing over the virtual line atthe cup side of the Stranger 1−Time of the nose crossing over thevirtual line at the cup side of the object)/(Time of the nose crossingover the virtual line at the cup side of the Stranger 1+Time of the nosecrossing over the virtual line at the cup side of theobject)}×100  <Equation 2>

Preference index (%)={(Time staying in Stranger 1 area−Time staying inthe Stranger 2 area)/(Time staying in Stranger 1 area+Time staying inthe Stranger 2 area)}×100  <Equation 3>

As a result, the time in which the IRSp53 deficient mouse stayed in theroom with the mouse was significantly less than the time of the normalmouse, and the time of directly applying the nose to sniff alsodecreased. In addition, the time of the direct action when noses makecontact with each other to sniff and the action of following one anotherwere measured, and compared to the normal mouse, the deficient mouseinteracted much less. Therefore, the sociability behavior beingseriously deficient in the IRSp53 deficient mouse was observed.

The IRSp53 deficient (KO) mice showed a lower preference for Stranger 1with respect to the object. This indicates that the IRSp53 deficientmice has a low sociability behavior. Meanwhile, in the experiment havingthe Stranger 1 and the Stranger 2, the IRSp53 (KO) mouse did not showmuch difference from the normal mouse, thus, this indicates that theIRSp53 deficient mouse and the other mouse are distinguishable. (A to Hof FIG. 2, WT: wild-type mice, KO: IRSp53 deficient mice, S: Stranger,S1: Stranger 1, S2: Stranger 2)

Experimental Example 2

From the result of the 3-chamber sociability test of Experimentalexample 1, the IRSp53 deficient mouse was identified as havingsociability behavior problems. Therefore, in the present Experimentalexample 2, whether the sociability behavior deficiency is restored whenthe NMDAR function in the IRSp53 deficient mice is suppressed wasevaluated. The sociability behavior restoring experiment was conductedas described below.

30 minutes before the 3-chamber sociability test, the memantine and theMPEP were intraperitoneally injected to identify the sociabilitybehavior. For reference, the memantine is the direct inhibitor of theNMDAR. In addition, the MPEP is an MGluR inhibitor and indirectlycontrols the NMDAR through the MGluR which is a glutamate receptor. Inthe present experiment, the memantine having a concentration of 10 mg/kgwas used and the MPEP having a concentration of 30 mg/kg was used. Inaddition, to eliminate the influence due to the intraperitonealinjection from the effect of the used drug, a saline solution in a sameamount of the drug (in other words, the memantine and the MPEP) wasintraperitoneally injected into mice as a control group, and the3-chamber sociability test was conducted as the control group.

As a result, the wild-type mice injected with the saline solution showeda preference of the normal mice, and a decrease in the mice preferencewas identified from the IRSp53 deficient mice injected with the salinesolution. Meanwhile, the IRSp53 deficient mouse injected with thememantine and the MPEP had a mice preference improved to a level of thewild-type mice and the restoration of the sociability was observed.Therefore, the sociability behavior deficiency symptom shown in theIRSp53 deficient mice restored to the behavior of the normal mice byinjecting the memantine and the MPEP was identified. The restorationeffect of both drugs was good and there were no sedation due to sideeffects (A and B of FIG. 3, and A to D of FIG. 4, FIG. 3 shows themovement of the mouse in the 3-chamber sociability test changed to aheat sensing signal, and FIG. 4 shows graphs of the time of the mouseactually staying in the box and the time actually exploring the mouse.)

<Experimental Example 3> Electrophysiological Measurement of the NMDARCharacteristic of a Nerve Cell of the IRSp53 Deficient Mouse

To observe whether the memantine and the MPEP restore the NMDAR functionobserved on the hippocampus of the IRSp53 deficient mice to a normalrange, the electrical signal flow of the synapses through the NMDAR wasmeasured by the electrophysiological experiment.

<3-1>

When the NMDAR is activated by electrically stimulating the never cell,an ion transferred from the outside of the nerve cell to the inside ofthe nerve cell through the NMDAR according to the activation levelexists, and by the ion concentration difference of the inside andoutside of the cell, various proteins inside the cell are alsoactivated, thereby showing electrical reaction of the nerve cell withrespect to the stimulation. The state in which this reaction ismaintained for 30 minutes or longer is called Long-term potentiation(LTP) and Long-term depression (LTD), and when the NMDAR is intensivelyactivated, the LTP may be induced, and when the NMDAR is weaklyactivated a long-term weakening, LTD may be induced.

In the present experiment, the Long-term potentiation (LTP) and theLong-term depression experiments were conducted. First, the NMDARproperties of the nerve cell of the IRSp53 deficient mice wereelectrophysiologically measured. The measurement was experimented andconducted by the method disclosed in the paper of Kim M H et al. (Kim,M. H. et al. Enhanced NMDA Receptor-Mediated Synaptic Transmission,Enhanced Long-Term Potentiation, and Impaired Learning and Memory inMice Lacking IRSp53. J Neurosci 29, 1586-1595, doi:Doi10.1523/Jneurosci.4306-08.2009 (2009)). The equipment used for theelectrophysiological measurement was MultiClamp 700B amplifier andAxopatch 200B of Molecular Devices, and Clampex 9.2 and Clampfit 9software of the same company were used. During the experiment, BX50WImicroscope of Olympus was used.

In the present experiment, first, for all of the electrophysiologicalexperiment, brain slices were made from the brains of the normal miceand the IRSp53 deficient mice. To make the slices, VT1200S modelvibratome of Leica was used. The Long-term potentiation (LTP) and theLong-term depression experiments used mice, which were 21 days to 28days from birth, and other electrophysiological experiments used micewhich were 14 days to 21 days from birth. The brain slices including thehippocampus portions of the mice were made in thicknesses of 300 to 400μm. During cutting of the slices, the brains were immersed in a colddissection buffer. The composition of the dissection buffer is asfollows: 212 mM of sucrose, 25 mM of NaHCO3, 5 mM of KCl, 1.25 mM ofNaH2PO4, 10 mM of D-glucose, 2 mM of sodium pyruvate, 1.2 mM of sodiumascorbate, 3.5 mM of MgCl2 and 0.5 mM of CaCl2. In addition, thedissection buffer was saturated by 95% O2/5% CO2 gas. The cut slices wasimmersed in an artificial cerebrospinal fluid of 32° C. and moved toroom temperature after restoration. The composition of the cerebrospinalfluid is as follows: 125 mM of NaCl, 25 mM of NaHCO3, 2.5 mM of KCl,1.25 mM of NaH2PO4, 10 mM of D-glucose, 1.3 mM of MgCl2 and 2.5 mM ofCaCl2.

The condition maintained for 30 minutes or more when a reaction occurafter the NMDAR is weakly stimulated is called NMDAR-LTD, and in thepresent experiment, the NMDAR function becomes excessive in the IRSp53deficient mouse, so when stimulated as same as the wild-type mice, aNMDAR-LTD reaction smaller than the reaction that should originallyoccur was induced. A weaker NMDAR-LTD is observed in the IRSp53deficient mouse compared to the normal mouse, and this was restoredthrough the memantine treatment (A to C of FIG. 5, WT: wild-type mice,KO: IRSp53 deficient mice). This indicates that the IRSp53 deficientmice has a problem in removing the NMDA receptor of the nerve cellsurface, so excessive NMDA receptors may exist on the surface.

<3-2>

The reactivity occurring when a specific membrane potential state, inwhich the NMDAR of the nerve cell is fired, is maintained is comparedwith the reactivity of AMPAR(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), whichis a Glutamate receptor, to evaluate the NMDA/AMRA ratio from which theamount of activation of the NMDAR may be identified.

As a result, in the case of the IRSp53 deficient mouse compared to thewild-type mouse, the NMDAR activation was excessive, so the NMDA/AMPAratio was increased. When the IRSp53 deficient mouse was treated withthe MPEP, the NMDA/AMPA ratio was restored to the level of the wild-typemouse (D and E of FIG. 5, WT: wild-type mice, KO: IRSp53 deficientmice). This result agrees with <3-1> using the memantine.

Experimental Example 4

The IRSp53 is the fifth most protein existing in the excitatorypostsynapse, and is a scaffolding protein directly and indirectlyinteracting with the neurotransmitter receptor and the signalingprotein. The IRSp53 is also known as BAIAP2. The IRSp53 is directlyconnected to many protein forming actin cytoskeletal, large amount ofwhich exist in the excitatory synapse and is required for specificallymaintaining the synaptic structure.

The brain slices including the hippocampus from each of the wild-typemouse and the IRSp53 deficient mouse were prepared, and theelectrophysiological equipment was used to induce a reaction stimulatingspecifically the NMDAR directly on each never cell.

As a result, in the wild-type mouse, the NMDAR function was activatednormally, thus the reaction was observed, whereas, in the IRSp53deficient mouse, about a 20% increased reaction compared to thewild-type mouse was observed (E of FIG. 5, comparison ofWT-Saline/KO-Saline NMDA/AMPA ratio). Therefore, in the IRSp53 deficientmouse, the NMDAR function was abnormally increased.

Experimental Example 5

<5-1>

In general, the medial prefrontal cortex (mPFC) is known to be importantas the brain region responsible for the sociability behavior. A chemicalproduct for fluorescence was filled in the nerve cell of the medialprefrontal cortex of the wild-type mouse and the IRSp53 deficient mouseand the structure and the form of the nerve cell were observed by afluorescence microscope.

In the nerve cell structure, when comparing the structure of dendritehaving the role of receiving the stimulation and information from thebrain, the development of the dendrite in the IRSp53 deficient mouse waslower than in the wild-type mouse (A and C of FIG. 6). Meanwhile, whenobserving the dendritic spine of the nerve cell by theelectrophysiological experiment, the IRSp53 deficient mouse had a lowerdevelopment of the dendritic spine of the nerve cell (D to F of FIG. 6).In addition, when the electrical reaction occurring by a voluntarysecretion of the glutamate without any stimulation to the nerve cell ismeasured, the number of the dendrite reacting to the glutamate may beinferred, based on this result and from observing the dendritic spinestructure of the nerve cell of the medial prefrontal cortex through anactual electron microscope, the number of the dendrite decreased in theIRSp53 deficient mice (G, H, I, J and K of FIG. 6).

Therefore, in the case of the IRSp53 deficient mouse, the excitatorysynapse structure was impaired, and the synaptic electrical signal andthe nerve cell firing were abnormal (A to K of FIG. 6).

<5-2>

The memantine was administered to the IRSp53 deficient mouse, and thesynapse of the medial prefrontal cortex was structurally andfunctionally analyzed. In the experiment, the brain slices were notmade, an anesthetic drug (1.5 g/kg) named Urethane was used on the mouseto perform the electrophysiological experiment in a condition in whichthe neural circuitry in the mouse is maintained, and the electricalsignal firing of the nerve cell was observed,

In detail, in the experiment, the mouse was anesthetized, a glasselectrode for measuring the electrical signal was inserted in the medialprefrontal cortex and the hippocampus, and measured. A and I of FIG. 7show the positions through which each electrode is inserted. From theresult of comparing the nerve cell firing of the medial prefrontalcortex of the IRSp53 deficient mouse, in the IRSp53 deficient mouse, thenerve cell firing of the medial prefrontal cortex decreased.Specifically, in the IRSp53 deficient mouse, the nerve cell firingspecific to the excitatory nerve cell decreased (B, C and D of FIG. 7).

The memantine was intraperitoneally injected (10 mg/kg) into the IRSp53deficient mice such that the nerve cell firing may be induced after 30minutes, and from the observation, the reactivity with respect to theIRSp53 deficient mouse was high and the drug showed good effects.

Meanwhile, in the case of the hippocampus, from the result of injectingthe memantine into the wild-type mouse and the IRSp53 deficient mouseand observing the nerve cell firing change, the firing was greater andthe showed better effect in the IRSp53 deficient mouse compared to thewild-type mice (J, K and L of FIG. 7).

Therefore, when the IRSp53 deficient mouse was treated with thememantine, the nerve cell firing of the medial prefrontal cortexrestored to the normal range (A to L of FIG. 7).

What is claimed is:
 1. A method for treating a mental disease havingenhanced N-methyl-D-aspartate (NMDA) receptor (NMDAR) function in apatient having the mental disease, the method comprising: administeringan NMDAR inhibitor composition to the patient.
 2. The method of claim 1,wherein the NMDAR inhibitor composition is selected from memantine,MPEP, MK-810, or AP5.
 3. The method of claim 1, wherein the mentaldisease comprises a sociability behavior deficiency symptom.
 4. Themethod claim 1, wherein the patient has a deficient IRSp53 gene.
 5. Themethod of claim 4, wherein the deficient IRSp53 gene does not expressthe IRSp53 protein.
 6. The method of claim 1, wherein the mental diseaseis selected from the group consisting of autism, schizophrenia, andattention deficit/hyperactivity disorder (ADHD).
 7. The method of claim1, wherein the NMDAR inhibitor composition comprises memantine.
 8. Themethod of claim 1, wherein the NMDAR inhibitor composition comprisesMPEP.
 9. A method for decreasing enhanced N-methyl-D-aspartate (NMDA)receptor (NMDAR) function in a patient having enhanced NMDAR function,the method comprising: administering an NMDAR inhibitor composition tothe patient.
 10. The method of claim 9, wherein the NMDAR inhibitorcomposition is selected from memantine, MPEP, MK-810, or AP5.
 11. Themethod of claim 9, wherein the patient has a deficient IRSp53 gene. 12.The method of claim 9, wherein the mental disease is selected from thegroup consisting of autism, schizophrenia, and attentiondeficit/hyperactivity disorder (ADHD).
 13. A method for treatingschizophrenia or attention deficit/hyperactivity disorder (ADHD) in apatient having schizophrenia or attention deficit/hyperactivity disorder(ADHD) and enhanced N-methyl-D-aspartate (NMDA) receptor (NMDAR)function, comprising: administering an NMDAR inhibitor composition tothe patient.
 14. The method of claim 13, wherein the patient has asociability behavior deficiency symptom.
 15. The method of claim 14,wherein the sociability behavior deficiency symptom includes socialinteraction deficiencies and social communication deficiencies.
 16. Themethod of claim 13, wherein the patient has a deficient IRSp53 gene. 17.The method of claim 16, wherein the deficient IRSp53 gene does notexpress the IRSp53 protein.
 18. The method of claim 13, wherein theNMDAR inhibitor composition comprises memantine, MPEP, MK-810, or AP5.19. The method of claim 13, wherein the NMDAR inhibitor composition ismemantine.
 20. The method of claim 13, wherein the NMDAR inhibitorcomposition is MPEP.